Osteoporosis (OP) is a major health problem affecting millions of Americans as they age because of its associated increased risk of bone fractures and death. It is associated with sex steroid deficiency and low-level chronic inflammation both of which increase with age and are accompanied by increased production of pro-inflammatory cytokines, including tumor necrosis factor (TNF). These cytokines stimulate the formation and bone destructive activity of osteoclasts (OCs), the cells that resorb (degrade) bone. Bisphosphonates (BPs) are currently the most widely prescribed drugs used to treat OP (Russell et al., 2008, Osteoporos Int 19:733-59). They inhibit the activity, but not the formation of OCs. Although they prevent bone loss and reduce fractures, poor patient compliance and more recent fears about side-effects have limited their use. In addition, many individuals are unaware that they have osteoporosis. Thus, many patients go untreated. Osteoporosis can also complicate inflammatory bone diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis, in which pro-inflammatory cytokine production is also increased.
RA patients can have devastating joint destruction and generalized and localized osteoporosis. They are treated with a variety of drugs to reduce inflammation and joint destruction, including corticosteroids, non-steroidal anti-inflammatory drugs, methotrexate and hydroxychloroquine (HCQ), and ultimately TNF inhibitors, but only 50-60% of patients achieve successful control of symptoms and signs of joint inflammation, despite the success of these combination therapies (Hyrich et al., 2006, Rheumatology 45:1558-65; Symmons and Silman, 2006, Lupus 15:122-6). HCQ and methotrexate act as anti-inflammatory drugs and their administration to patients who move on to TNF inhibitors typically is continued. However, the mechanism of action of HCQ is poorly understood and it also has side-effects, including blindness in up to 0.5-1% of patients (Motten et al., 1999, Photochem Photobiol 69:282-7; Costedoat-Chalumeau et al., 2015, Clin Rev Allergy Immunol). HCQ replaced chloroquine (CQ) decades ago for treatment of RA in the US and Europe because HCQ has a lower toxicity profile, including less damage to the eye and other tissues. Recently it was reported that CQ prevents bone resorption and osteoporosis in mouse models of postmenopausal osteoporosis and hyperparathyroidism (Xiu Y et al., 2014, J Clin Invest 124:297-310). Unlike CQ, HCQ does not prevent bone resorption in mice, and there are no definitive data showing that either of these drugs has anti-resorptive effects in humans. CQ is still widely prescribed in many 3rd world countries because it is much cheaper than HCQ. Furthermore, only 50-60% of RA patients respond successfully to these treatments. Thus, there is an unmet need to improve efficacy of existing drugs and develop new approaches to therapy.
Recent attempts to target estrogen analogs (Morioka et al., 2010, Bioorg Med Chem 18:1143-8), antibiotic agents (Tanaka et al., 2010, Bioorg Med Chem Lett 20:1355-9), and prostaglandins (Arns et al., 2012, Bioorg Med Chem 20:2131-40) to bone with BPs through carbamate linker conjugation have been successful, specifically through chemical linkages that allow subsequent release of an active agent at the bone surface. This approach improved the efficacy of estradiol to inhibit bone resorption, while limiting side-effects, such as endometrial hyperplasia (Morioka et al., 2010, Bioorg Med Chem 18:1143-8). In a related effort, this BP-drug conjugation technology facilitated adequate delivery to bone and slow release of prostaglandin “warheads” in radiolabelled PK studies to estimate concentrations of delivered drug (Arns et al., 2012, Bioorg Med Chem 20:2131-40). Carbamate linkers are cleaved by enzymatic or by hydrolytic means in the acidic microenvironment under the osteoclast ruffled border in bone resorption sites, thus releasing the active drug (“warhead/payload”) (Arns et al., 2012, Bioorg Med Chem 20:2131-40).
Bisphosphonates have been used for decades to treat osteoporosis and reduce fracture rates in the aging population (Wasnich and Miller, 2000, J Clin Endocrinol Metab 85:231-6; Cummings et al., 2002, Am J Med 112:281-9). However, poor patient compliance and more recent fears about side-effects with BPs, including osteonecrosis and atypical fractures, have limited their use, and thus many patients go untreated (Rasmusson and Abtahi, 2014, Int J Dent 2014:471035; Kennel and Drake, 2009, Mayo Clin Proc 84:632-7). More recently, Denosumab, an anti-RANKL antibody has been developed and has anti-resorptive efficacy similar to that of BPs (Scottt, 2014, Drugs Aging 31:555-76; Mandema et al., 2014, J Clin Endocrinol Metab 99:3746-55). However, prescription of Denosumab has lagged behind expectations and therefore has not filled this gap in therapy. Thus, there is a need to develop new therapies to treat this disease as the aging population increases. Patients with RA also develop systemic as well as localized osteoporosis around affected joints, in part as a result of the effects of the increased levels of pro-inflammatory/osteoclastogenic cytokines and also because of the adverse effects of corticosteroids on the skeleton (Hoes et al., 2015, Expert Opin Pharmacother 16:559-71; Watt et al., 2014, Joint Bone Spine 81:347-51). Patients on long-term steroid treatment also require effective anti-resorptive therapy, but few patients receive them during the early years of their disease when they can lose significant amounts of bone. Most RA patients are treated with HCQ, but if it does not have anti-resorptive activity in humans, similar to findings in mice, it will not help prevent this bone loss.
There is a need in the art for new compounds and methods that selectively target the delivery of compounds, such as CQ specifically to bone tissue in order to ameliorate and/or prevent the toxic side effects arising from systemic distribution and to make dose escalation possible in order to improve therapeutic outcomes. The present invention fulfills this need.